We and others have demonstrated that transforming growth factor b (TGFb) acts as a tumor suppressor in colon cancer, and that mutation or loss of TGFb receptors leads to tumor progression. Our preliminary studies indicate that loss of TGFb signaling is associated with increased metastasis. However, the mechanisms of TGFb-mediated suppression of metastasis remain largely unknown. Aberrant cell survival under stress conditions has been implicated in metastasis. We have shown that loss of TGFb signaling confers resistance to growth factor deprivation stress (GFDS)-induced apoptosis as well as anoikis (apoptosis induced by loss of contact with extracellular matrix or through binding to an inappropriate integrin). These novel findings suggest that TGFb tumor suppression involves suppression of survival of pre-malignant and/or early stage tumor cells in response to environmental stress, and that loss of TGFb signaling enables aberrant activation of survival pathways, which would contribute to metastasis. Identification of survival pathways activated by suppression of TGFb signaling will provide novel targets for preventing and/or treating metastatic cancer in patients with dysfunctional TGFb signaling. The objective of this application is to test the central hypothesis that the metastatic phenotype of colon cancer is dependent upon aberrant cell survival conferred by activation of oncogenic pathways resulting from inactivation of TGFb signaling. Ron kinase (recepteur d'origine nantais) is a member of the Met proto-oncogene family. Ron has not been previously linked to TGFb suppression. Our preliminary results show that: 1) TGFb down-regulates Ron expression; 2) Ron expression confers stress resistance in colon cancer cells; and 3) Knockdown of Ron kinase reduces metastasis in an orthotopic model of colon cancer. However, the mechanisms by which Ron activation contributes to cell survival and metastasis of colon cancer cells are not well understood. We will determine these mechanisms in this proposal. Integrins are cell-surface receptors that bind to extracellular matrix (ECM) and mediate cell adhesion. We have shown that TGFb signaling negatively mediates integrin a5 expression in colon cancer cells and that ectopic expression of integrin a5 protects cells from stress-induced apoptosis. Furthermore, integrin a5 has been implicated as a survival factor in many cell types. It has been previously shown that integrin a5 expression is associated with tumor progression in colon cancer cells and that increased integrin a5 expression leads to increased tumorigenicity in vivo. We will therefore test the hypothesis that integrin a5 is a determinant of metastasis in colon cancer and determine the underlined mechanisms. Elucidation of the reciprocal relationship among TGFb, Ron and integrin a5 as well as the role of their interplay in cell survival and metastasis will facilitate our understanding of the mechanisms of TGFb tumor suppression and develop novel and efficient therapeutic strategies.